Osteosclerotic metaphyseal dysplasia is a unique form of osteopetrosis characterized by dysplasiaof metaphyses of tubular bones with increased bone density. By exome sequencing, we found a homozygous mutation, c.5938_5944del[p.E1980Afs*66]in LRRK1 (Leucin-rich repeat kinase 1). LRRK1 was highly expressed in differentiated osteoclast. The patient’s phenotype was very similar to that of Lrrk1 knockout mice that we […]
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Gain-of-function mutation in TRPV4 identified in patients with osteonecrosis of the femoral head
Osteonecrosis of the femoral head is a painful and debilitating bone disease that causes bone death at the hip leading to its collapse and subsequent end-stage osteoarthritis. The disease is poorly understood limiting treatment options to invasive surgical procedures such as total hip replacement. We have identified a Canadian family of Greek origin with osteonecrosis […]
Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos
An essential feature of successful mammalian reproduction is the fusion of a sperm with a mature oocyte. We previously found that heterozygous mutations in TUBB8 caused oocyte maturation arrest. In this study, we identified novel heterozygous and homozygous mutations in TUBB8 that cause variability in the corresponding phenotypes of human oocytes and early embryos. For […]
Genes associated with common variable immunodeficiency: one diagnosis to rule them all?
Common variable immunodeficiency (CVID) is an immune disorder characterized by low antibody levels and an increased susceptibility to infections and immune-related complications. It is a heterogeneous disorder with a variable clinical presentation and severity. Thus far, single gene defects have been identified in about 2-10% of patients. As more disease genes are being identified, it […]
A Splicing Mutation in VPS4B Causes Dentin Dysplasia I
Dentin dysplasia I (DDI) is an autosomal dominant disorder characterized by rootless teeth with abnormal pulpal morphology. The etiology of DDI still remains largely unclear. Here, we identified VPS4B as a disease-causing gene for DDI by linkage analysis followed by deep sequencing of the candidate genes in a large Chinese family with DDI. A splicing mutation (IVS7+46C>G) […]
GATOR1 complex: the common genetic actor in focal epilepsies
mTOR is a critical effector of cell signaling, playing a pivotal role in regulating physiology of the whole body, including the brain. Mutations in genes encoding GATOR1 complex, an inhibitor of mTOR activity, have been recently implicated in the pathogenesis of a wide spectrum of focal epilepsies (FEs), occasionally associated with malformations of cortical development. […]
New paradigms for BRCA1/BRCA2 testing in women with ovarian cancer: results of the Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study
Many women diagnosed with epithelial ovarian cancer do not access genetic testing for BRCA1/2 mutations. The reasons for this are complex but may in part be due to lack of awareness or an over-complicated referral pathway. The Genetic Testing in Epithelial Ovarian Cancer (GTEOC) study looked at a streamlined approach led by Oncology and coordinated […]
Mutations in CEP120 cause Joubert syndrome as well as complex ciliopathy phenotypes
Ciliopathies are an extensive group of disorders with considerable genetic and clinical overlap, which collectively share multiple organ involvement and may result in lethal or viable phenotypes. In large numbers of cases the genetic defect remains yet to be determined. Our study resulted in the identification of six probands carrying nine distinct mutations (of which […]
When chromatin organisation floats astray: the Srcap gene and Floating–Harbor syndrome
Floating-Harbor syndrome (FHS) is a rare human disease characterized by developmental defects, often associated with mental retardation. FHS was first described at Boston’s Floating Hospital in 1973, but the causative gene, called Srcap, was identified only recently. Srcap encodes a protein with a key role in control of gene expression, however, the underlying molecular bases […]
A recurrent mitochondrial p.Trp22Arg NDUFB3 variant causes a distinctive facial appearance, short stature and a mild biochemical and clinical phenotype
Mitochondrial diseases occur when insufficient energy is produced, affect both adults and children and often require a muscle biopsy to help the investigation and diagnosis. We have identified the same genetic defect – a mutation within the NDUFB3 gene – in ten children from eight families with identical physical features; affected children are short, have […]